2010 Grants - Du

2010 New Investigator Research Grant

Mitochondria are cellular structures that use oxygen and nutrients to produce energy for a cell. In early Alzheimer's disease, however, mitochondrial function becomes inhibited. At the same time in this disease process, the brain loses synapses, or tiny channels through which neurons send and receive chemical messages. Both mitochondrial dysfunction and synaptic loss become worse as Alzheimer's progresses, suggesting that these pathologies affect cognitive decline and other aspects of dementia.

In recent studies with mice engineered to express Alzheimer-like symptoms, Heng Du, M.D., Ph.D., and colleagues found that mitochondria developed pores in their membranes. These pores were created, in part, through the activity of a membrane compound called cyclophilin D. Ultimately, the exposed mitochondria became dysfunctional in the mice. Dr. Du's team also found that by inhibiting the activity of cyclophilin D, they could moderate mitochondrial dysfunction and prevent cognitive declines associated with synaptic loss.

For this proposed effort, Dr. Du and colleagues will use cultured cells and Alzheimer-like mice to determine how mitochondrial pores lead to synaptic damage. Their effort will involve studies of compounds involved in synaptic health, including the protein fragment beta-amyloid—a key suspect in Alzheimer's disease. Dr. Du's team will also study whether mitochondrial pores block the activity of an enzyme called cAMP-dependent protein kinase (PKA), which has been shown to prevent disease-related cognitive decline. The researchers hope to determine whether promoting PKA activity might help ameliorate the harmful effects of cyclophilin D and mitochondrial pores.

The results of this effort could clarify our understanding of how cognitive decline occurs in Alzheimer's. The work could also lead to novel drug therapies for the disease.